Analyses of Cost-Effectveness of Migraine Therapies Should Consider Mutiple Measures

dard costs applied to health care resource use. The Ellis manuscript is not very transparent on how costs were attributed except that a panel determined it. They may have attributed costs to AD/E based on ICD-9 codes other than those we used. Furthermore, we most probably used a different method of assessing severity than the method used in the international study cited. Also, we included individuals with private insurance in our study; thus, our study population probably had different characteristics from the sample used in the ISAAC study. Therefore, it is difficult to compare our findings to those of Ellis et al. Lastly, our previous analyses did attempt to quantitate the effects of this illness on quality of life. 3,4 Indeed, using Pearson correlation coefficients, we found that visit count correlated moderately well with the results of the Dermatology Life Quality Index (r=0.33; P=0.0006). Taken together, all of our results, in concert with those of Ellis and colleagues, would indeed indicate that AD might impose a significant financial and humanistic burden on society.


■■ Analyses of Cost-Effectiveness of Migraine Therapies Should Consider Multiple Measures Dear Editor,
This letter is in response to the article on the relative cost-effectiveness of triptans by Dr. Adelman and Mr. Belsey that appeared in the January/February 2003 issue of JMCP. 1 I believe their conclusions may be misleading because they are based on an oversimplified analysis of cost-effectiveness.
In order to calculate comparative triptan costs, the authors evaluated only 1 efficacy endpoint: the percentage of patients who were pain-free at 2 hours. Their rationale for focusing on this endpoint alone was that IHS guidelines identify the 2-hour pain-free endpoint as the most important endpoint and that patients have identified complete pain relief as their most important concern. However, patients rate "no recurrence of migraine" almost as high as they rate initial pain relief. 2,3 Furthermore, when doing a cost analysis, there is a need to focus on other endpoints. At a minimum, the total cost of treating a migraine attack for 24 hours (not just 2 hours) should be evaluated. Most patients who have a recurrence of moderate or severe migraine will remedicate with either a repeat dose of triptan or with another medication, thus increasing the overall 24-hour cost.
Recurrence rates from published double-blind studies range from 7% to 47%, depending on the particular triptan and study. 4 The authors, based on an analysis of 2-hour pain-free response rates alone, suggest that rizatriptan (10 mg) is the most cost-effective triptan, but rizatriptan has been associated with recurrence rates in the 35% to 47% range. They also suggest, based on 2-hour pain-free response, that frovatriptan (2.5 mg) is the least cost-effective triptan; however, frovatriptan has lower recurrence rates in the 7% to 25% range.
Migraine recurrence is costly from a number of perspectives. A second or a third dose of a triptan (or other medication) taken within a single 24-hour period increases the "out-of-pocket" medication costs to patients and the reimbursement costs to insurers. Office visits and even emergency room visits may be required for particularly long-lasting, refractory attacks. Employers bear some of the costs from an extended migraine attack in the form of lost productivity. For most migraine sufferers, hours 3 through 24 of the attack (and beyond) can be more costly than the initial 2 hours in terms of both the financial and physical burden of migraine.
Variability in recurrence and remedication rates must be taken into account in order to obtain a reasonable estimate of triptan cost-effectiveness. If a single endpoint is to be used to calculate cost-effectiveness, the 24-hour response endpoint may be most appropriate. The impact of remedication as a result of recurrence is accounted for in measures of 24-hour sustained relief (moderate or severe pain reduced to no or mild pain with no recurrence or remedication within 24 hours) or 24-hour sustained pain freedom (moderate or severe pain reduced to no pain with no recurrence and no remedication). These endpoints are now recognized as the most important clinical and pharmacoeconomic endpoints. 5 Neither of these endpoints has been consistently reported in the clinical-trial literature. 5,6 Two recent meta-analyses have attempted to evaluate them. In a meta-analysis of 24-hour sustained relief, 5 only 3 of the currently marketed triptans (rizatriptan 10 mg, sumatriptan 50 mg and 100 mg, and zolmitriptan 5 mg) were included. At the time this meta-analysis was performed, the other triptans did not have published data available on sustained relief. In a separate meta-analysis that evaluated 24-hour sustained pain-free response, all but one of the triptans (frovatriptan) were included. 6 However this endpoint could only be calculated for some of the 53 trials that were identified for the primary meta-analysis; the actual number of trials included is not reported. Therefore it would not be appropriate to make comparisons across the entire triptan class based on either of these meta-analyses.
It is currently not reasonable to undertake a single endpoint meta-analysis in order to determine relative cost-effectiveness of the triptans. In addition, the cost of adverse events should be included. Some triptans have higher adverse-event rates than others. 7 A sensible approach to cost-effective migraine treatment requires stratification based on the patient' s migraine history and particular attack characteristics. Patients with short-duration migraine do well using triptans that deliver freedom from pain within 2 hours. Patients who are more susceptible to recurrence and adverse events might find it more cost effective to use triptans with less recurrence and fewer adverse events.
Stephen D. Silberstein

The Authors Respond
We thank Dr. Silberstein for his carefully constructed comments regarding our article on the relative cost-effectiveness of triptans. 1 His criticism of the piece offers some interesting notes concerning the methodology of cost-effectiveness analyses. Silberstein writes that our paper is "misleading" due to "an oversimplified analysis of cost-effectiveness." His argument rests on 3 pivots: (a) the choosing of an inappropriate endpoint, (b) the excluding of recurrence rates, and (c) the ignoring of adverse events. Responding to these points will allow us to clarify our methodological motivations.
Silberstein criticizes the choice of the 2-hour pain-free endpoint, the industry standard. It does not take into account recurrence, the return of a moderate or severe headache within 24 hours. 2 Recurrence, as Silberstein points out, is a persistent problem from the perspective of effectiveness of treatment as well as cost.
Recurrence data derived from randomized controlled trials should be used with caution. Although comparing recurrence rates appears to offer clinically useful information, the lack of a consistently used definition of recurrence invalidates such comparisons. Recurrence figures also tend to be derived from a selected subset of patients-those who initially responded to treatment-rather than the entire intention-to-treat population. 3 The resultant corruption of randomization means that any conclusions will be prone to significant bias. 4 Silberstein suggests using the "24-hour sustained pain-freedom" endpoint instead of 2-hour pain free. We agree that the 24-hour data is a quality gauge of sustained migraine relief. We explained in the original paper, "The endpoint of '24-hour sustained pain free' could also have been used in this meta-analysis. It would have produced data similar to the 'pain-free' data presented." 1 We based this statement on the strong correlation (R 2 =0.89 for Ferrari' s meta-analysis 5 between the 2 endpoints.
Unfortunately, sustained response only constitutes a primary outcome measure in a very small number of triptan studies. Estimates of these rates found in the literature generally relate to post hoc analyses of previously published data rather than results derived from primary data gathering. 3 The potential for bias is therefore considerable. 4 Although Ferrari' s analysis confirms a strong concordance between these 2 outcomes, when examining older studies, the 2-hour response offers the more statistically rigorous results.
Recently, Reeder conducted a cost-effectiveness study based on the 24-hour sustained pain-free endpoint, which confirmed our prediction of parallel cost-effectiveness for the 2 endpoints. 6 In both studies, almotriptan and rizatriptan were the most cost effective, while naratriptan was the least cost effective (among the triptans included in both; frovatriptan did not have published 24-hour sustained pain-free data).
Reeder' s analysis indicates that sustained pain-free status depends more heavily on response than on recurrence. Lack of initial effect, therefore, would be expected to cause more multi-Letters ple dosing than would recurrence. Pascual' s triptan per-attack study verifies this idea. 7 His results indicate that rizatriptan, with its large response rates, has a significantly lower incidence of attacks treated with multiple tablets than does sumatriptan, zolmitriptan, and naratriptan in spite of relatively high recurrence rates.
Simply, recurrence is a poor endpoint. We would recommend that studies not report recurrence rates; instead, they should use 24-hour sustained pain relief or 24-hour sustained pain free to indicate the long-term efficacy of acute medications.
Like recurrence, adverse events were not included in the original analysis because they do not clarify or alter the costeffectiveness of the medications. In addition, it would not have been statistically valid to include the measure in our analysis. No published triptan study has measured adverse events as a primary outcome. Although it is certainly possible to pool such data as exists in order to define a "number needed to harm," 4 inconsistent recording of adverse events and very wide confidence intervals mean that these findings are of limited value when comparing alternative treatments.
Triptans are consistently well tolerated. 8,9 Most adverse effects are mild and have no related costs. Even the once-feared side effects of neck and chest tightness do not trigger cardiac evaluation as they once did. These side effects are not thought to be related to cardiac events.
There seems to be no correlation between the adverse effects and safety of triptans, nor is there any evidence of safety differences among triptans. The impact of side effects on cost is inconsequential compared to migraine disability considerations.
To conclude, we chose the 2-hour pain-free data because it was the industry standard, 10 matched the desires of patients, 11,12 mirrored 24-hour sustained pain-free results, 6 and minimized the risk of introducing bias into our conclusions. 4 Including recurrence rates and adverse events in the analysis would not have significantly altered the results, only added complicating factors.
Again, we thank Dr. Silberstein for his comments.  1 and editorial 1 in the Journal. There are real and presumably unintended consequences of the HIPAA statute and regulations.

James U. Adelman, MD
I was looking for a new car. I decided to be patriotic and avoid German cars-the Russians and French long ago sinking into the oblivion of instant lemons-due to the antiwar stances being taken by our former enemies/charity recipients/allies. However, before I could leave the office, I had an inch-thick pile of HIPAA compliance policies and forms to review and frantic administrators calling in panic and fear about the impending invasion of trial lawyers and bureaucrats looking for HIPAA compliance gotchas over which to sue. Also, in the local paper, Los Angeles County announced it was closing a dozen or more primary care clinics to save money, while, in another article in a trade rag, there was mention of the fact that L.A. County had just announced it had signed agreements with consultants totaling $16 million to prepare the county for HIPAA. The more I thought, the more angry I became over the fed' s heavy-handed, dogmatic, and ignorant approach to confidentiality.
Here we are with literally hundreds of years of experience with the doctor-patient relationship and its spillover, and relatively stringent laws in almost every state governing the use and release of patient information, panicked over HIPAA. We have a government of know-nothing technocrats who are blindly marching to the drum of regulations that ignore the reality of medical practice, with providers left to wonder about the costs and aftereffects of the federal mandates. Suddenly, I had a little empathy for the Germans. While I agree with our stance toward Iraq, I can't help thinking that the Europeans' complaints about Bush' s foreign policy sound all too familiar when walking the Letters